Developing a Minimally Immunogenic Humanized Antibody by SDR Grafting

  • Syed V. S. Kashmiri
  • Roberto De Pascalis
  • Noreen R. Gonzales
Part of the Methods in Molecular Biology™ book series (MIMB, volume 248)

Abstract

Since the advent of hybridoma technology a quarter century ago, a large number of murine monoclonal antibodies (MAbs) have been developed that are potentially useful clinical reagents against human infectious diseases and cancers. However, the clinical value of murine antibodies is limited because of the human anti-murine antibody (HAMA) response they evoke in patients (1, 2, 3, 4). Early attempts to reduce the HAMA response led to the development of mouse-human chimeric MAbs that are generated by replacing the constant regions of the heavy and light chains of the murine antibodies with those of the human antibodies (5). Another approach to reducing the immunogenicity of a murine antibody is to resurface or veneer its variable domains. This is accomplished by replacing the exposed residues in the framework region of the murine antibody with the residues that are present in the corresponding positions of human antibodies (6). A more commonly used procedure for the reduction of HAMA response involves grafting of the complementarity-determining regions (CDRs) of the xenogeneic antibody onto the human antibody frameworks, while retaining those residues of the xenogeneic framework regions that are considered essential for antibody reactivity to its antigen (7) (see  Chapter 7). Following this approach, several xenogeneic antibodies have been successfully humanized (8).

References

  1. 1.
    Seccamani, E., Tattanelli, M., Mariani, M., Spranzi, E., Scassellati, G. A., and Siccardi, A. G. (1989) A simple quantitative determination of human antibodies to murine immunoglobulins (HAMA) in serum samples. Nucl. Med. Biol. 16, 167–170.Google Scholar
  2. 2.
    Reynolds, J. C., DelVecchio, S., Sakahara, H., and Lora, M. (1989) Anti-murine response to mouse monoclonal antibodies. Nucl. Med. Biol. 16, 121–125.Google Scholar
  3. 3.
    Colcher, D., Milenic, D. E., Ferroni, P., Carrasquillo, J. A., Reynolds, J. C., Roselli, M., et al. (1990) In vivo fate of monoclonal antibody B72.3 in patients with colorectal cancer. J. Nucl. Med. 31, 1133–1142.PubMedGoogle Scholar
  4. 4.
    Blanco, I., Kawatsu, R., Harrison., K., Leichner, P., Augustine, S., Baranowska-Kortylewicz, J., Tempero, M., and Colcher, D. (1997) Antiidiotypic response against murine monoclonal antibodies reactive with tumor-associated antigen TAG-72. J. Clin. Immunol. 17, 96–106.PubMedCrossRefGoogle Scholar
  5. 5.
    Morrison, S. L. and Schlom, J. (1990) Recombinant chimeric monoclonal antibodies in Important Advances in Oncology (Rosenberg, S. A., ed.), J. B. Lippincott, Philadelphia, PA, pp. 3–18.Google Scholar
  6. 6.
    Padlan, E. A. (1991) A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties. Mol. Immunol. 28, 489–498.PubMedCrossRefGoogle Scholar
  7. 7.
    Winter, G. and Harris, W. J. (1993) Humanized antibodies. Immunol. Today. 14, 243–246.PubMedCrossRefGoogle Scholar
  8. 8.
    Carter, P. (2001) Improving the efficacy of antibody-based cancer therapies. Nature Rev./Cancer 1, 118–129.CrossRefGoogle Scholar
  9. 9.
    Singer, I. I., Kawka, D. W., DeMartino, J. A., Daugherty, B. L., Elliston, K. O., Alves, K., et al. (1993) Optimal humanization of 1B4, an anti-CD18 murine monoclonal antibody, is achieved by correct choice of human V-region framework sequences. J. Immunol. 150, 2844–2857.PubMedGoogle Scholar
  10. 10.
    Hakimi, K., Chizzonite, R., Luke, D. R., Familletti, P. C., Bailon, P., Kondas, J. A., et al. (1991) Reduced immunogenicity and improved phamacokinetics of humanized anti-Tac in cynomolgus monkeys. J. Immunol. 147, 1352–1359.PubMedGoogle Scholar
  11. 11.
    Schneider, W. P., Glaser, S. M., Kondas, J. A., and Hakimi, J. (1993) The anti-idiotypic response by cynomolgus monkeys to humanized anti-Tac is primarily directed to complementarity-determining regions H1, H2, and L3. J. Immunol. 150, 3086–3090.PubMedGoogle Scholar
  12. 12.
    Stephens, S., Emitage, S., Vetterlein, O., Chaplin, L., Bebbinton, C., Nesbitt, A., et al. (1995) Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology 85, 668–674.PubMedGoogle Scholar
  13. 13.
    Sharkey, R. M., Juweid, M., Shevitz, J., Behr, T., Dunn, R., Swayne, L. C., et al. (1995) Evaluation of a complementarity-determining region-grafted (humanized) anti-carcinoembryonic antigen monoclonal antibody in preclicinal and clinical studies. Cancer Res. 55, 5935s–5945s.PubMedGoogle Scholar
  14. 14.
    Iwahashi, M., Milenic, D. E., Padlan, E. A., Bei, R., Schlom, J., and Kashmiri, S.V.S. (1999) CDR substitutions of a humanized monoclonal antibody (CC49): Contributions of individual CDRs to antigen binding and immunogenicity. Mol. Immunol. 36, 1079–1091.PubMedCrossRefGoogle Scholar
  15. 15.
    Glaser, S. M., Vasquez, M., Payne, P. W., and Schneider, P. W. (1992) Dissection of the combining site in a humanized anti-Tac antibody. J. Immunol. 149, 2607–2614.PubMedGoogle Scholar
  16. 16.
    Sompuram, S. R., Den, W., and Sharon, J. (1996) Analysis of antigen binding and idiotypic expression by antibodies with polyglycine-replaced complementarity-determining regions. J. Immunol. 156, 1071–1081.PubMedGoogle Scholar
  17. 17.
    Padlan, E. A. (1994) Anatomy of an antibody molecule. Mol. Immunol. 31, 169–217.PubMedCrossRefGoogle Scholar
  18. 18.
    Padlan, E. A., Abergel, C., and Tipper, J. P. (1995) Identification of specificity-determining residues in antibodies. FASEB J. 9, 133–139.PubMedGoogle Scholar
  19. 19.
    Tamura, M., Milenic, D. E., Iwahashi, M., Padlan, E. A., Schlom, J., and Kashmiri, S.V.S. (2000) Structural correlates of an anticarcinoma antibody: Identification of specificity-determining residues (SDRs) and development of a minimally immunogenic antibody variant by retention of SDRs only. J. Immunol. 164, 1432–1441.PubMedGoogle Scholar
  20. 20.
    Jones, P. T., Dear, P. H., Foote, J., Neuberger, M. S., and Winter, G. (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522–525.PubMedCrossRefGoogle Scholar
  21. 21.
    Riechman, L., Clark, M., Waldmann, H., and Winter, G. (1988) Reshaping human antibodies for therapy. Nature 332, 323–327.CrossRefGoogle Scholar
  22. 22.
    Bernstein, F. C., Koetzle, T. F., Williams, G. J., Meyer, E. F. Jr., Brice, M. D., Rodgers, J. R., et al. (1977) The Protein Data Bank: a computer-based archival file for macromolecular structures. J. Mol. Biol. 112, 535–542.PubMedCrossRefGoogle Scholar
  23. 23.
    Abola, E. E., Sussman, J. L., Prilusky, J., and Manning, N. O. (1997) Protein Data Bank archives of three-dimensional macromolecular structures. Methods Enzymol. 277, 556–571.PubMedCrossRefGoogle Scholar
  24. 24.
    Benson, D. A., Karsch-Mizrachi, I., Lipman, D. J., Ostell, J., Rapp, B. A., and Wheeler, D. L. (2002) GenBank. Nucleic Acids Res. 30, 17–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Stoesser, G., Baker, W., van den Broek, A., Camon, E., Garcia-Pastor, M., Kanz, C., et al. (2002) The EMBL Nucleotide Sequence Database. Nucleic Acids Res. 30, 21–26.PubMedCrossRefGoogle Scholar
  26. 26.
    Bairoch, A. and Apweiler, R. (2000) The SWISS-PROT protein sequence database and its supplement TrEMBL in 2000. Nucleic Acids Res. 28, 45–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Wu, C. H., Huang, H., Arminski, L., Castro-Alvear, J., Chen, Y., Hu, Z. Z., et al. (2002) The Protein Information Resource: an integrated public resource of functional annotation of proteins. Nucleic Acids Res. 30, 35–37.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosok, M. J., Yelton, D. E., Harris, L. J., Bajorath, J., Hellstrom, K. E., Hellstrom, I., et al. (1996) A combinatorial library strategy for the rapid humanization of anticarcinoma BR96 Fab. J. Biol. Chem. 271, 22,611–22,618.PubMedCrossRefGoogle Scholar
  29. 29.
    Caldas, C., Coelho, V. P., Rigden, D. J., Neschich, G., Moro, A. M., and Brigido, M. M. (2000) Design and synthesis of germline-based hemi-humanized single-chain Fv against the CD18 surface antigen. Protein Eng. 13, 353–360.PubMedCrossRefGoogle Scholar
  30. 30.
    Queen, C., Schneider, W. P., Selick, H. E., Payne, P. W., Landolfi, N. F., Duncan, J. F., et al. (1989) A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. USA 86, 10,029–10,033.CrossRefGoogle Scholar
  31. 31.
    Tempest, P. R., White, P., Buttle, M., Carr, F. J., and Harris, W. J. (1995) Identification of framework residues required to restore antigen binding during reshaping of a monoclonal antibody against the glycoprotein gB of human cytomegalovirus. Int. J. Biol. Macromol. 17, 37–42.PubMedCrossRefGoogle Scholar
  32. 32.
    De Pascalis, R., Makoto, I., Tamura, M., Padlan, E. A., Gonzales, N. R., Santos, A. D., et al. (2002) Grafting of “abbreviated” CDRs containing specificity determining residues (SDRs) essential for ligand contact to engineer a less immunogenic humanized mAb. J. Immunol. 169, 3076–3084.PubMedGoogle Scholar
  33. 33.
    Landt, O., Grunert, H.-P., and Hahn, U. (1990) A general method for rapid site-directed mutagenesis using the polymerase chain reaction. Gene 96, 125–128.PubMedCrossRefGoogle Scholar
  34. 34.
    Pavlinkova, G., Colcher, D., Booth, B.J.M., Goel, A., and Batra, S. K. (2001) Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-TAG-72 single-chain Fvs. Int. J. Cancer 94, 717–726.PubMedCrossRefGoogle Scholar
  35. 35.
    Gonzales, N. R., Schuck, P., Schlom, J., and Kashmiri, S.V.S. (2002) Surface plasmon resonance-based competition assay to assess the sera reactivity of variants of humanized antibodies. J. Immunol. Methods 268, 197–210.PubMedCrossRefGoogle Scholar
  36. 36.
    Hearn, M. T., Bethell, G. S., Ayers, J. S., and Hancock, W. S. (1979) Application of 1,1′-carbonyldiimidazole-activated agarose for the purification of proteins. II. The use of an activated matrix devoid of additional charged groups for the purification of thyroid proteins. J. Chromatogr. 185, 463–470.PubMedCrossRefGoogle Scholar
  37. 37.
    Abrantes, M., Magone, M. T., Boyd, L. F., and Schuck, P. (2001) Adaptation of a surface plasmon resonance biosensor with microfluidics for use with small sample volumes and long contact times. Anal. Chem. 73, 2828–2835.PubMedCrossRefGoogle Scholar
  38. 38.
    Gilligan, J. J., Schuck, P., and Yergey, A. L. (2002) Mass spectrometry after capture and small volume elution of analyte from a surface plasmon resonance biosensor surface. Anal. Chem. 74, 2041–2047.PubMedCrossRefGoogle Scholar
  39. 39.
    Kabat, E. A., Wu, T. T., Perry, H. M., Gottesman, K. S., and Foeller, C. (eds.) (1991) Sequences of Proteins of Immunological Interests, 5th ed., US Department of Health and Human Service, National Institute of Health, Bethesda, MD (NIH Publication No. 91-3242).Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2004

Authors and Affiliations

  • Syed V. S. Kashmiri
    • 1
  • Roberto De Pascalis
    • 1
  • Noreen R. Gonzales
    • 1
  1. 1.Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesda

Personalised recommendations